The overall objective of this project is to use total lymphoid irradiation (TLI) to prevent rejection of kidney allografts in outbred dogs. The long-term goal is to develop a protocol that will be practical for the application of TLI in the treatment of human renal allograft recipients. The proposed experiments have two basic aims: 1) to use TLI as a generalized immunosuppressive treatment, alone and in combination with pharmacologic immunosuppresson; and 2) to determine whether TLI in combination with donor bone marrow administration can induce specific tolerance in recipient dogs with indefinite survival of the renal allograft. This latter approach will also be tested alone and in combination with other agents. The experiments of the second aim will include observations on the development of chimerism and graft versus host disease. We plan to vary the dose of TLI and either azathioprine or cyclosporin A (CsA) to achieve graft prolongation with less morbidity. We shall continue to test bone marrow administration as a possible adjuvant. This will be done in conjunction with either TLI or anti-thymocyte serum (ATS). GVHD may be prevented by the latter or by administration of CsA. Because of higher rejection rate associated with cadaveric transplants when compared to well matched living related donors and because of short notice that accompanies the cadaver transplant, we will evaluate the potential for post-transplant TLI accompanied by ATS or pharmacological immunosuppression. This may permit the potential benefits of TLI to accrue without necessity of treatment prior to transplantation. The ultimate goal is to have a treatment with a better therapeutic ratio than that currently provided by conventional immunosuppressive therapy to prevent allograft rejection.